The PI3K–AKT pathway has pleiotropic effects and its inhibition has long been of interest in the management of prostate cancer, where a compensatory increase in PI3K signaling has been reported following androgen receptor (AR) blockade. Prostate cancer cells can also bypass AR blockade through induction of other hormone receptors, in particular the glucocorticoid receptor (GR). Here we demonstrate that AKT inhibition significantly decreases cell proliferation through both cytostatic and cytotoxic effects. The cytotoxic effect is enhanced by AR inhibition and is most pronounced in models that induce compensatory GR expression. AKT inhibition increases canonical AR activity and remodels the chromatin landscape, decreasing enhancer interaction at the GR gene (NR3C1) locus. Importantly, it blocks induction of GR expression and activity following AR blockade. This is confirmed in multiple in vivo models, where AKT inhibition of established xenografts leads to increased canonical AR activity, decreased GR expression, and marked antitumor activity. Overall, our results demonstrate that inhibition of the PI3K/AKT pathway can block GR activity and overcome GR-mediated resistance to AR-targeted therapy. Ipatasertib is currently in clinical development, and GR induction may be a biomarker to identify responsive patients or a responsive disease state.

中文翻译：

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靶向 PI3K/AKT 通路通过抑制糖皮质激素受体的诱导克服恩杂鲁胺耐药

PI3K-AKT 通路具有多效性，其抑制作用长期以来在前列腺癌的治疗中备受关注，据报道，在雄激素受体 (AR) 阻断后 PI3K 信号传导补偿性增加。前列腺癌细胞还可以通过诱导其他激素受体，特别是糖皮质激素受体 (GR) 来绕过 AR 阻断。在这里，我们证明 AKT 抑制通过细胞生长抑制和细胞毒性作用显着降低细胞增殖。AR 抑制增强了细胞毒性作用，并且在诱导代偿性 GR 表达的模型中最为明显。AKT 抑制会增加典型的 AR 活性并重塑染色质景观，减少 GR 基因 (NR3C1) 基因座的增强子相互作用。重要的，它在 AR 阻断后阻断 GR 表达和活性的诱导。这在多个体内模型中得到证实，其中已建立的异种移植物的 AKT 抑制导致典型 AR 活性增加、GR 表达降低和显着的抗肿瘤活性。总的来说，我们的结果表明抑制 PI3K/AKT 通路可以阻断 GR 活性并克服 GR 介导的对 AR 靶向治疗的抵抗。Ipatasertib 目前处于临床开发阶段，GR 诱导可能是识别反应性患者或反应性疾病状态的生物标志物。我们的结果表明，PI3K/AKT 通路的抑制可以阻断 GR 活性并克服 GR 介导的对 AR 靶向治疗的抗性。Ipatasertib 目前处于临床开发阶段，GR 诱导可能是识别反应性患者或反应性疾病状态的生物标志物。我们的结果表明，PI3K/AKT 通路的抑制可以阻断 GR 活性并克服 GR 介导的对 AR 靶向治疗的抗性。Ipatasertib 目前处于临床开发阶段，GR 诱导可能是识别反应性患者或反应性疾病状态的生物标志物。